The goal of our SCOR (Molecular Genetics of Hypertension in Mexican Americans) is to identify genes which influence blood pressure, and thus, are responsible for the development of hypertension. Substantial evidence for the importance of insulin resistance in hypertension, as well as the high prevalence of insulin resistance in the Mexican American population has led us to place great emphasis on the examination of insulin resistance as an intermediate phenotype for hypertension in this ethnic group. We will determine how insulin resistance interacts with other important physiologic mechanisms, particularly salt sensitivity, in affecting blood pressure by examining the relationships of these phenotypes in individuals at high risk for hypertension (i.e. the young adult offspring of affected individuals) as well as by examining familial clustering of insulin resistance with specific combinations of other intermediate phenotypes. Project 1 will provide the detailed physiologic data which is so necessary for successful identification of genes and gene regions which will be performed in Project 2, using both systematic mapping and candidate gene approaches. The extensive phenotyping of 800-1000 individuals from 200 Mexican American families with hypertension will provide a truly unique resource for the investigation of the genetic basis of hypertension in Mexican Americans. The studies performed up to now have relied upon either large numbers of individuals who have undergone only limited evaluation or upon intensive investigation of relatively small numbers of individuals from a limited number of families. The in-depth investigation conducted in specific intermediate phenotypes and large numbers of families will generate and afford much greater power in finding the individual genes for hypertension in this population. Projects 3, 4, and 5 (the Molecular Physiology Module) will utilize animal models to further investigate the pathophysiology and etiology of hypertension, providing additional insights into candidate genes which should be investigated in humans and also clarifying the physiology behind genetic loci which are linked to human hypertension. The combination of detailed human phenotypic studies, comprehensive genetic mapping, and careful animal model investigations outlined in this SCOR provides a powerful, multidimensional approach to the genetics of blood pressure regulation, hypertension and insulin resistance.